tbuckley/cabot-search huggingface dataset:
Von Hippel–Lindau disease: insights into oxygen sensing, protein degradation, and cancer
Authors: William G. Kaelin
Journal: Journal of Clinical Investigation (2022)

Germline loss-of-function mutations of the VHL tumor suppressor gene cause von Hippel-Lindau disease, which is associated with an increased risk of hemangioblastomas, clear cell renal cell carcinomas (ccRCCs), and paragangliomas. This Review describes mechanisms involving the VHL gene product in oxygen sensing, protein degradation, and tumor development and current therapeutic strategies targeting these mechanisms. The VHL gene product is the substrate recognition subunit of a ubiquitin ligase that targets the α subunit of the heterodimeric hypoxia-inducible factor (HIF) transcription factor for proteasomal degradation when oxygen is present. This oxygen dependence stems from the requirement that HIFα be prolyl-hydroxylated on one (or both) of two conserved prolyl residues by members of the EglN (also called PHD) prolyl hydroxylase family. Deregulation of HIF, and particularly HIF2, drives the growth of VHL-defective ccRCCs. Drugs that inhibit the HIF-responsive gene product VEGF are now mainstays of ccRCC treatment. An allosteric HIF2 inhibitor was recently approved for the treatment of ccRCCs arising in the setting of VHL disease and has advanced to phase III testing for sporadic ccRCCs based on promising phase I/II data. Orally available EglN inhibitors are being tested for the treatment of anemia and ischemia. Five of these agents have been approved for the treatment of anemia in the setting of chronic kidney disease in various countries around the world.
A world without tuberculosis: moving from imagination to reality
Authors: William R. Jacobs
Journal: Journal of Clinical Investigation (2022)

Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, remains a leading cause of death from an infectious agent, resulting in more than a million deaths per year. Despite vaccines and chemotherapies, patients often harbor persister M. tuberculosis cells that resist immune assault and chemotherapeutic treatments, resulting in a latent TB infection (LTBI). In this issue of the JCI, Sharan et al. used an aerosol-based macaque model to show that weekly treatments with isoniazid and rifapentine for 3 months reduced active M. tuberculosis infection and LTBI. Lung tissue from treated animals showed fewer granulomas when compared with the untreated control animals. These findings suggest that it is possible to eliminate persister M. tuberculosis cells, thereby eliminating LTBI. If similar elimination routinely occurs in patients undergoing the isoniazid and rifapentine treatment, the hidden reservoir of M. tuberculosis associated with LTBI would be greatly reduced, allowing us to imagine, and eventually achieve, a world without TB.
A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML
Authors: Arsene Mekinian, Lin Pierre Zhao, Sylvie Chevret, Kristell Desseaux, Laurent Pascal, Thibaut Comont, Alexandre Maria, Pierre Peterlin, Louis Terriou, Maud D’Aveni Piney, Marie-Pierre Gourin, Norbert Vey, Odile Beyne Rauzy, Vincent Grobost, Holy Bezanahary, Sophie Dimicoli-Salazar, Anne Banos, Stefan Wickenhauser, Benoit De Renzis, Eric Durot, Shanti Natarajan-Amé, Laurent Voillat, Fatiha Chermat, Karine Lemaire, Vincent Jachiet, Chantal Himberlin, Sylvain Thépot, Jose Miguel Torregrosa Diaz, Laurent Frenzel, Emmanuel Gyan, Guillaume Denis, Pierre Hirsch, Olivier Kosmider, Lionel Ades, Olivier Fain, Pierre Fenaux
Journal: Leukemia (2022)
Use of Mendelian randomization to better understand and treat sepsis
Authors: James A. Russell, Nuala J. Meyer, Keith R. Walley
Journal: Intensive Care Medicine (2022)

Discovering novel therapies and defining the causal contribution of genes, proteins and lipids is challenging in sepsis, because sepsis is so heterogeneous; effective therapies in one patient may not be effective in another, explaining in part why sepsis trials have not been very successful.We highlight Mendelian randomization (MR), a statistical methods that first helps establish causal relationships between intermediate phenotypes such as plasma proteins and clinical phenotypes using genetics.In sepsis, there are innumerable studies showing significant associations between proteins, metabolites, other biomarkers and outcomes, yet the causal contribution of biomarkers is highly uncertain, potentially due to confounding, reverse causation, or because, for example, inflammatory markers are non-specific epiphenomena.Genetics are a powerful tool to interrogate which intermediate traits, including plasma proteins, metabolites, or even radiographic features, contribute to a disease.MR also enhances prognostic and predictive enrichment of sepsis trials by better defining biologically relevant clinical subgroups.The technique has been successfully used to define several traits with causal contributions to risk for acute respiratory distress syndrome (ARDS) [1-3] and to sepsis mortality [4,5], highlighting pathways which warrant targeting and identifying specific at-risk populations.Thus, MR holds promise to advance successful precision sepsis trials.
Critical Role of <scp>LMCD1</scp> in Promoting Profibrotic Characteristics of Lung Myofibroblasts in Experimental and Scleroderma‐Associated Lung Fibrosis
Authors: Galina S. Bogatkevich, Ilia Atanelishvili, Andrew M. Bogatkevich, Richard M. Silver
Journal: Arthritis & Rheumatology (2022)

Objective Interstitial lung disease (ILD) is a serious complication and leading cause of mortality in patients with systemic sclerosis (SSc). In this study, we explored the role of LIM and cysteine‐rich domains protein 1 (LMCD1) as a novel factor in the pathogenesis of SSc‐related ILD (SSc‐ILD). Methods The expression and effects of LMCD1 were studied in lung tissue samples and fibroblasts from SSc‐ILD patients and control subjects as well as in lung tissue samples from animal models. Results LMCD1 was consistently elevated in lung tissue samples and in fibroblasts isolated from SSc‐ILD patients as compared to controls. Additionally, LMCD1 was found to be highly expressed in the lung in the fibroblast‐specific protein (FSP)–driven, constitutively active transforming growth factor β receptor type I (TGFβR1) transgenic mouse model of ILD and the bleomycin‐induced mouse model of ILD. In lung fibroblasts from SSc‐ILD patients, LMCD1 is an essential factor for the TGFβ‐induced generation of type I collagen, fibronectin, and α‐smooth muscle actin (α‐SMA). Depletion of LMCD1 by small interfering RNA reduced the expression of extracellular matrix proteins and lowered transcriptional activity and expression of α‐SMA, as well as decreased the proliferation and contractile activity of SSc‐ILD lung fibroblasts. In dense fibrotic areas of affected lung tissue, lung LMCD1 colocalized with α‐SMA. In cultured scleroderma lung fibroblasts, LMCD1 colocalized and interacted with serum response factor which mediates LMCD1‐induced contractile activity of lung fibroblasts. Conclusion Our study identifies LMCD1 as a profibrotic molecule contributing to the activation of myofibroblasts and the persistent fibroproliferation observed in SSc‐ILD. Thus, LMCD1 may be a potential novel therapeutic target for patients with SSc‐ILD.
Seronegative coeliac disease and non-coeliac enteropathies: precision medicine, precision medicine, where are you?
Authors: Knut E A Lundin, Peter HR Green
Journal: Gut (2022)

<b>OBJECTIVE:</b> To determine the relationship between urinary tract infection UTI on admission and ischemic strokes related to atrial fibrillation (AFib). <b>BACKGROUND:</b> Many of the inflammatory markers have been repeatedly found elevated with AFib, and been specifically linked to the hypercoaguable state of AFib and the risk of stroke. Elevated inflammatory markers are commonly seen in infections. UTI has been adequately studied as a complication of stroke. Yet, the relationship between UTI on admission and the risk for stroke has been previously suggested, but never been thoroughly investigated. <b>DESIGN/METHODS:</b> A retrospective study of cardioembolic stroke patients who were admitted between 2011-2013. Inclusion criteria included admissions of ischemic stroke proven by imaging studies in patients who had documented AFib and urinanalysis UA on presentation. Chi-square test and t-test were used to analyze the difference of the UTI+ group versus UTI- group. UTI was defined as WBC &gt; 5 cells in pre-catheterization UA. <b>RESULTS:</b> A total of 163 admissions met the inclusion criteria of whom 44 were found to have UTI on admission [27[percnt], 95[percnt] CI (20.16-33.8)]. Age, CHAD score and other stroke risk factors did not differ significantly between groups, but the female sex ,expectedly, was more common in the UTI+ group [0.3 in females versus 0.17 in males, p=0.15] . Mean NIHSS was slightly higher but did not differ significantly between UTI+ versus UTI- groups [9.67 vs 8.16, respectively. Mean difference 1.518, 95[percnt] CI (-4.12-1.08) p=0.25]. <b>CONCLUSIONS:</b> UTI on admission is a common finding in ischemic stroke admissions secondary to Afib and may be seen in up to 27[percnt] of these cases. Although the stroke risk factors and severity, as determined by NIHSS, did not differ between groups, more studies may be warranted to compare the eventual impact of UTI in AFib-related strokes to other types of strokes. <b>Disclosure:</b> Dr. Zidan has nothing to disclose. Dr. A_Nasany has nothing to disclose. Dr. Bedair has nothing to disclose. Dr. Bragin has nothing to disclose. Dr. Kamel has nothing to disclose.
Topical, immunomodulatory epoxy-tiglianes induce biofilm disruption and healing in acute and chronic skin wounds
Authors: Lydia C. Powell, Jason K. Cullen, Glen M. Boyle, Tom De Ridder, Pei-Yi Yap, Wenya Xue, Carly J. Pierce, Manon F. Pritchard, Georgina E. Menzies, Muthanna Abdulkarim, Jennifer Y. M. Adams, Joana Stokniene, Lewis W. Francis, Mark Gumbleton, Jenny Johns, Katja E. Hill, Adam V. Jones, Peter G. Parsons, Paul Reddell, David W. Thomas
Journal: Science Translational Medicine (2022)

The management of antibiotic-resistant, bacterial biofilm infections in chronic skin wounds is an increasing clinical challenge. Despite advances in diagnosis, many patients do not derive benefit from current anti-infective/antibiotic therapies. Here, we report a novel class of naturally occurring and semisynthetic epoxy-tiglianes, derived from the Queensland blushwood tree (Fontainea picrosperma), and demonstrate their antimicrobial activity (modifying bacterial growth and inducing biofilm disruption), with structure/activity relationships established against important human pathogens. In vitro, the lead candidate EBC-1013 stimulated protein kinase C (PKC)-dependent neutrophil reactive oxygen species (ROS) induction and NETosis and increased expression of wound healing-associated cytokines, chemokines, and antimicrobial peptides in keratinocytes and fibroblasts. In vivo, topical EBC-1013 induced rapid resolution of infection with increased matrix remodeling in acute thermal injuries in calves. In chronically infected diabetic mouse wounds, treatment induced cytokine/chemokine production, inflammatory cell recruitment, and complete healing (in six of seven wounds) with ordered keratinocyte differentiation. These results highlight a nonantibiotic approach involving contrasting, orthogonal mechanisms of action combining targeted biofilm disruption and innate immune induction in the treatment of chronic wounds.
Dual spike and nucleocapsid mRNA vaccination confer protection against SARS-CoV-2 Omicron and Delta variants in preclinical models
Authors: Renee L. Hajnik, Jessica A. Plante, Yuejin Liang, Mohamad-Gabriel Alameh, Jinyi Tang, Srinivasa Reddy Bonam, Chaojie Zhong, Awadalkareem Adam, Dionna Scharton, Grace H. Rafael, Yang Liu, Nicholas C. Hazell, Jiaren Sun, Lynn Soong, Pei-Yong Shi, Tian Wang, David H. Walker, Jie Sun, Drew Weissman, Scott C. Weaver, Kenneth S. Plante, Haitao Hu
Journal: Science Translational Medicine (2022)

Emergence of SARS-CoV-2 variants of concern (VOCs), including the highly transmissible Omicron and Delta strains, has posed constant challenges to the current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified messenger RNA (mRNA) vaccine that expresses the more conserved viral nucleoprotein (mRNA-N) and show that mRNA-N vaccination alone can induce modest control of SARS-CoV-2. Critically, combining mRNA-N with the clinically proven S-expressing mRNA vaccine (mRNA-S+N) induced robust protection against both Delta and Omicron variants. In the hamster models of SARS-CoV-2 VOC challenge, we demonstrated that, compared to mRNA-S alone, combination mRNA-S+N vaccination not only induced more robust control of the Delta and Omicron variants in the lungs but also provided enhanced protection in the upper respiratory tract. In vivo CD8
A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections
Authors: Mark A. T. Blaskovich, Karl A. Hansford, Mark S. Butler, Soumya Ramu, Angela M. Kavanagh, Angie M. Jarrad, Anggia Prasetyoputri, Miranda E. Pitt, Johnny X. Huang, Fredrik Lindahl, Zyta M. Ziora, Tanya Bradford, Craig Muldoon, Premraj Rajaratnam, Ruby Pelingon, David J. Edwards, Bing Zhang, Maite Amado, Alysha G. Elliott, Johannes Zuegg, Lachlan Coin, Anne-Kathrin Woischnig, Nina Khanna, Elena Breidenstein, Anna Stincone, Clive Mason, Nawaz Khan, Hye-Kyung Cho, Melissa J. Karau, Kerryl E. Greenwood-Quaintance, Robin Patel, Mandy Wootton, Meagan L. James, Melanie L. Hutton, Dena Lyras, Abiodun D. Ogunniyi, Layla K. Mahdi, Darren J. Trott, Xiaoqian Wu, Samantha Niles, Kim Lewis, Jordan R. Smith, Katie E. Barber, Juwon Yim, Seth Alan Rice, Michael J. Rybak, Chad R. Ishmael, Kellyn R. Hori, Nicholas M. Bernthal, Kevin P. Francis, Jason A. Roberts, David L. Paterson, Matthew A. Cooper
Journal: Science Translational Medicine (2022)

Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria ( Staphylococcus aureus and Streptococcus pneumoniae ) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC 90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae , as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics.
Practical Pedodontia or Juvenile Operative Dentistry and Public Health Dentistry. An Introductory Text for Students and Practitioners of Dentistry.
Journal: JAMA (1927)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Chronic Venous Disease
Authors: John J. Bergan, Geert W. Schmid-Schönbein, Philip D. Coleridge Smith, Andrew N. Nicolaides, Michel R. Boisseau, Bo Eklof
Journal: New England Journal of Medicine (2006)

This account of chronic venous disease summarizes the clinical aspects of the disorder and reviews the recent advances in studies of the hydrodynamic and biochemical changes that underlie the disorder.
Anti-Spike Mucosal IgA Protection against SARS-CoV-2 Omicron Infection
Authors: Sebastian Havervall, Ulrika Marking, Julia Svensson, Nina Greilert-Norin, Philip Bacchus, Peter Nilsson, Sophia Hober, Max Gordon, Kim Blom, Jonas Klingström, Mikael Åberg, Anna Smed-Sörensen, Charlotte Thålin
Journal: New England Journal of Medicine (2022)

nated, 0 to 13 days, 14 to 27 days, 1 to 2 months, 3 to 4 months, 5 to 6 months, 7 to 8 months, or ≥9 months).Among the patients who had received two doses of vaccine, waning of effectiveness against hospitalization was evident as early as 3 to 4 months after vaccination during both periods when the omicron sublineages were dominant.The vaccine effectiveness was 56.3% (95% confidence interval [CI], 51.6 to 60.5) during the BA.1-BA.2wave and 47.4% (95% CI, 19.9 to 65.5) during the BA.4-BA.5 wave (Table 1).Although boosting with a third dose maintained vaccine effectiveness against severe disease caused by all four sublineages at 1 to 2 months, the vaccine effectiveness had decreased by 3 to 4 months to an effectiveness of 50.0%(95% CI, 4.4 to 73.9) during the BA.1-BA.2wave and 46.8% (95% CI, 35.3 to 56.2) during the BA.4-BA.5 wave.Thus, after either two doses or three doses of the BNT162b2 vaccine, we found rapid waning of vaccine effectiveness against the current sublineages of the omicron variant with respect to protection against hospitalization.Our data indicate that boosting maintains vaccine effectiveness against severe disease caused by the current omicron sublineages, although the evidence of rapid waning of durability indicates the need for regular boosting as early as 4 months after the last dose or the need for vaccines to incorporate variants of concern to maintain protection.
Flaws in Mortality Data
Authors: Sheldon Greenfield
Journal: JAMA (1988)

Recent public releases of hospital mortality data have sparked debate over methods to identify poor-quality care. We examined variations among hospitals in patient characteristics known independently to affect the risk of adverse outcomes and focused on patient comorbidity, defined as the state of health at admission apart from the primary diagnosis. Data from a study of 2935 incident cancer patients treated in seven Southern California hospitals revealed substantial variations among hospitals in age, cancer stage, and the burden of comorbid conditions. In the highest-ranked hospital, 17.9% of patients had high levels of comorbidity, compared with 9.3% in the lowest-ranked hospital. The three hospitals with the highest comorbidity were also identified as high-mortality outliers in a recent California report on hospital mortality rates. We conclude that comorbidity must be considered in any hospital quality assessment method based on patient outcome. If it is not considered, variations in referral and admission patterns may be misinterpreted as differences in hospital quality. (<i>JAMA</i>1988;260:2253-2255)
The Regionalization of Perinatal Services
Authors: Marie C. McCormick
Journal: JAMA (1985)

The success of modern perinatal management techniques has led to the recommendation of the regional organization of perinatal services. This report summarizes the evaluation of a national demonstration program of such regionalization that was funded by the Robert Wood Johnson Foundation (RWJF) in 1975. In both funded regions and comparison areas, the neonatal mortality rates decreased sharply over the decade of the 1970s. This decline was linked to shifts in the hospital of delivery that indicated antepartum risk identification and transfer of management of high-risk pregnancies to tertiary centers for delivery, a change in service pattern consistent with some aspects of regionalization. The centralization of high-risk deliveries appeared so widespread that the special effect of the RWJF program could not be detected. Surveys of surviving 1-year-old infants showed that the decrease in neonatal mortality was accompanied by a decrease in selected morbidity. (<i>JAMA</i>1985;253:799-804)
Prevalence and clinical manifestation of Borrelia miyamotoi in Ixodes ticks and humans in the northern hemisphere: a systematic review and meta-analysis
Authors: Dieuwertje Hoornstra, Tal Azagi, Jacqueline A van Eck, Alex Wagemakers, Joris Koetsveld, René Spijker, Alexander E Platonov, Hein Sprong, Joppe W Hovius
Journal: The Lancet Microbe (2022)

Various studies have evaluated the infection of Ixodes ticks and humans with the relapsing fever spirochaete Borrelia miyamotoi. However, to our knowledge, the prevalence of infection and disease has not been assessed systematically. We aimed to examine the prevalence of B miyamotoi in Ixodes ticks and humans, and the disease it can cause, in the northern hemisphere.For this systematic review and meta-analysis, we searched PubMed and Web of Science up to March 1, 2021. Studies assessing Ixodes tick infection published since Jan 1, 2011 were eligible, whereas no time limitation was placed on reports of human infection and disease. We extracted B miyamotoi test positivity ratios and used a random-effects model to calculate estimated proportions of infected ticks, infected humans, and human disease with 95% CI. This study was registered with PROSPERO, CRD42021268996.We identified 730 studies through database searches and 316 additional studies that referenced two seminal articles on B miyamotoi. Of these 1046 studies, 157 were included in the review, reporting on 165 637 questing ticks, 45 608 unique individuals, and 504 well described cases of B miyamotoi disease in humans. In ticks, the highest prevalence of B miyamotoi was observed in Ixodes persulcatus (2·8%, 95% CI 2·4-3·1) and the lowest in Ixodes pacificus (0·7%, 0·6-0·8). The overall seroprevalence in humans was 4·4% (2·8-6·3), with significantly (p<0·0001) higher seroprevalences in the high-risk group (4·6%, 2·6-7·1), participants with confirmed or suspected Lyme borreliosis (4·8%, 1·8-8·8), and individuals suspected of having a different tick-borne disease (11·9%, 5·6-19·9) than in healthy controls (1·3%, 0·4-2·8). Participants suspected of having a different tick-borne disease tested positive for B miyamotoi by PCR significantly more often than did the high-risk group (p=0·025), with individuals in Asia more likely to test positive than those in the USA (odds ratio 14·63 [95% CI 2·80-76·41]).B miyamotoi disease should be considered an emerging infectious disease, especially in North America and Asia. Prospective studies and increased awareness are required to obtain further insights into the burden of disease.ZonMW and the European Regional Development Fund (Interreg).
35P Targeting the secreted gelsolin-DNGR-1 dendritic cell axis to enhance anti-cancer therapies
Authors: K.H.J. Lim, E. Giampazolias, O. Schulz, N.C. Rogers, A.C. Wilkins, E. Sahai, J. Strid, C. Reis e Sousa
Journal: Annals of Oncology (2022)